Neonatal stress modulates sickness behavior

The quality of the early environment, especially during the neonatal period, influences the development of individual differences in resistance to stress and illness in adulthood. A previous study demonstrated that neonatal stress augmented proinflammatory cytokine expression and viral replication in influenza virus-infected adult mice. The goal of the following study was to examine the lifelong effects of neonatal stress on the behavioral response to an immune challenge. Neonatal stress consisted of separating mouse pups from their dams (maternal separation, MSP) at critical points of their development. In the first study, pups were separated from the dam daily for 6 h between postnatal day 1 and 14. As adults, these mice were infected with influenza A/PR8 virus. In a second study, a similar paradigm of MSP was employed, and as adults mice were injected with lipopolysaccharide (LPS) (ip). In a third study pups were separated from the dam for 24 h on postnatal day 4 or 9. As adults, these mice received ip injections of LPS. In all three studies, changes in body weight, food and sweet solution consumption were examined following immune challenge. As previously described, activation of the immune system using influenza virus infection or LPS administration resulted in sickness behavior that consisted of body weight loss, anorexia and reduced consumption of a sweet solution. Furthermore, neonatal stress induced more rapid kinetics of sickness behavior and augmented several aspects of these symptoms. Together with previous studies, these findings suggest that neonatal stress disrupted the regulation of innate resistance to an immune challenge resulting in enhanced immunological and behavioral responses to immune activation. Thus, long lasting effects of early stress events may be the basis for individual differences in health and susceptibility to disease.     

Neonatal immune challenge affects the regulation of estrus cyclicity and feeding behavior in female rats

A single immune challenge with lipopolysaccharide (LPS) in the neonatal period has a long-lasting influence on immune response. Using female Sprague–Dawley rats, we examined whether neonatal LPS challenge influences the life-long neuroendocrine sensitivity of reproductive function and feeding behavior to LPS, and whether stress-related neuropeptides and their receptors are involved in neonatal LPS-induced physiological change. On day 10 after birth, all pups were injected with LPS (100 μg/kg, i.p.) or saline. Then, in Experiment 1, LPS (100 μg/kg, i.p.) or saline was injected at diestrous in adulthood, and the length of the estrous cycle, 24 h food intake and body weight change were recorded. In Experiment 2, the mRNA expression levels of corticotropin-releasing hormone (CRH), urocortin (UCN), urocortin 2 (UCN2), CRH receptor type 1 (CRH-R1) and CRH receptor type 2 (CRH-R2) in the hypothalamus were measured using real-time PCR. LPS injection in adulthood prolonged the estrous cycle in neonatal LPS-injected rats. LPS injection in adulthood decreased food intake and body weight in both neonatal LPS- and saline-injected rats, more so in the latter. Basal expressions of UCN2 and CRH-R2 mRNA were higher in neonatal LPS-injected rats than in saline-injected rats. These findings indicate that neonatal immune challenge influences the anti-stress regulation of the estrous cycle and feeding behavior in adulthood. Increased expression of UCN2 and CRH-R2 might enhance the sensitivity of the estrous cycle in suppressing the effects of LPS.     

Neonatal bacterial meningitis in southern Taiwan

To determine the epidemiologic trends, prognostic factors, and therapeutic results of neonatal bacterial meningitis, 60 neonatal patients with culture-proven neonatal bacterial meningitis were enrolled in this study. To compare changes over time, the appearance of disease among the patients was divided into two equal periods (1986-1993 and 1994-2001). Group B streptococci were the most common causative pathogens, accounting for approximately 32% of the episodes. Escherichia coli, the next most common pathogen, was more frequently observed in the second period. Seventy-seven percent of gram-negative bacilli isolates were resistant to ampicillin. Moreover, oxacillin-resistant Staphylococcus and ampicillin-resistant group B streptococci strains occurred in the second periods as late-onset neonatal bacterial meningitis. The overall mortality rates for the first and second study period were 17% and 8%, respectively. However, if individuals with poor outcomes were taken into account, 38% of patients were considered treatment failures. Significant prognostic factors included the presence of seizures, thrombocytopenia, and high cerebrospinal fluid protein and low cerebrospinal fluid glucose concentration. Although the mortality rate was significantly reduced in the second period, there has been increasing incidence of the emergence of resistant strains presenting a therapeutic challenge. The presentation in neonatal bacterial meningitis might be nonspecific, and blood culture results were negative in 45% of the episodes. Early diagnosis, choice of appropriate antibiotics, and correction of metabolic derangement are essential to improving outcomes.     

Congenital blindness, porencephaly, and neonatal thrombocytopenia: a report of four cases

Four unrelated infants with neonatal thrombocytopenia associated with congenital blindness and porencephaly have been seen over an 18-year period. The association of congenital blindness with neonatal thrombocytopenia has not previously been reported. All children had clinical purpura in the neonatal period; in three cases, thrombocytopenia was confirmed, while in one case, the diagnosis of thrombocytopenia was presumptive; in two cases, there was evidence of circulating maternal serum platelet isoantibodies. Extensive investigation for intrauterine infection was negative in the three cases with confirmed thrombocytopenia. The thrombocytopenia resolved spontaneously after the neonatal period. It is postulated that the porencephalies were the consequence of prenatal cerebrovascular episodes. The etiology of the optic atrophy is unclear. Serial cranial ultrasound investigation is recommended for all neonates with thrombocytopenia, even if neurologically asymptomatic in the neonatal period, and serial prenatal cranial ultrasound investigation is recommended for infants of mothers with a history of having previously had infants with neonatal isoimmune thrombocytopenia.     

Neonatal lipopolysaccharide exposure attenuates the homotypic stress-induced suppression of LH secretion in adulthood in male rat

Neonatal immune challenges have a long-lasting influence on immune response. Using male Sprague–Dawley rats, we examined whether neonatal lipopolysaccharide (LPS) challenge alters the sensitivity of male reproductive function to adult LPS challenge and at which level (central or testes) the alteration occurs. We also examined the mRNA expression of proinflammatory cytokines in the hypothalamus and testes because they have a pivotal role in immune stress-induced suppression of gonadotropin secretion and testosterone synthesis. On day 10 after birth, all the pups were injected with LPS (100 μg/kg, i.p.) or saline. Thereafter, LPS (100 μg/kg, i.p.) or saline was injected in adulthood at 8 weeks of age. The serum LH concentration was decreased by LPS injection during adulthood in the neonatal saline-injected rats. This suppressive effect was not seen in the neonatal LPS-injected rats. The serum testosterone concentration was decreased by adult LPS injection in both the neonatal LPS-injected and neonatal saline-injected rats. The expression levels of KiSS-1, which encodes kisspeptin, known to have a crucial role in the regulation of gonadotropin secretion, and GnRH mRNA in the hypothalamus and LHβ mRNA in the pituitary were not influenced by neonatal or adult LPS injection. On the other hand, the expression levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) mRNA in the hypothalamus and testes were increased by adult LPS injection in both the neonatal LPS-injected and neonatal saline-injected rats. Furthermore, the expression levels of these factors in the hypothalamus after adult LPS injection were significantly lower in the neonatal LPS-injected rats than in the neonatal saline-injected rats. These findings indicate that neonatal LPS challenge reduces the sensitivity of male reproductive function to the suppressive effects of LPS, mainly at the central level. Attenuation of proinflammatory cytokine synthesis in the hypothalamus might be involved in this alteration.     

Neonatal dexamethasone treatment induces long-lasting changes in T-cell receptor vbeta repertoire in rats

Glucocorticoids are frequently administered for the prevention of chronic lung disease in infants with respiratory distress syndrome. However, neonatal treatment may have consequences for immune functioning in the long-term. Here we demonstrate that neonatal glucocorticoid treatment has long-lasting effects on mRNA expression of several Vbeta genes within the CD4 and CD8 T cell subset in rats. Changes in the peripheral T cell Vbeta repertoire may be a consequence of altered intrathymic selection events in which corticosterone plays an important role. Indeed, here we show that neonatal glucocorticoid treatment affects corticosterone production by thymic epithelial cells during neonatal life. In conclusion, changes in T cell Vbeta repertoire after neonatal glucocorticoid treatment may contribute to altered immune reactivity in later life.     

Treatment of seizures in the neonate: Guidelines and consensus-based recommendations—Special report from the ILAE Task Force on Neonatal Seizures

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic–ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options.     

Neonatal Programming by Neuroimmune Challenge: Effects on Responses and Tolerance to Septic Doses of Lipopolysaccharide in Adult Male and Female Rats

A mild immune challenge experienced during the neonatal period leads to attenuated febrile responses to a similar challenge experienced later in life. However, the immune response to an endotoxin differs depending upon the severity of the challenge and it is not clear whether a neonatal immune challenge will also affect responses to a severe, potentially life‐threatening stimulus, such as sepsis. In the present study, we examined the effects of a neonatal immune challenge with lipopolysaccharide (LPS) on adult sickness responses, as well as the development of endotoxin tolerance, to a septic dose (1 or 3 mg/kg) of the same LPS in male and female rats. We demonstrate significant differences, particularly in males, in the fever profiles of neonatally LPS‐treated rats compared to neonatally saline‐treated controls. Specifically, male rats treated neonatally with LPS have reduced hypothermic and enhanced hyperthermic responses to both septic doses of LPS in adulthood. A somewhat different profile is seen in females, with neonatally LPS‐treated females having reduced hypothermia and enhanced hyperthermia compared to controls with 1 mg/kg but no differences with 3 mg/kg LPS. The results obtained demonstrate that alterations in innate immune responses previously reported for low doses of LPS can, for the most part, also be observed after severe immune challenge in later life.     

Neonatal overfeeding by small‐litter rearing sensitises hippocampal microglial responses to immune challenge: Reversal with neonatal repeated injections of saline or minocycline

The early‐life period is extremely vulnerable to programming effects from the environment, many of which persist into adulthood. We have previously demonstrated that adult rats overfed as neonates have hypothalamic microglia that are hyper‐responsive to an immune challenge, as well as hippocampal microglia that respond less efficiently to learning. We therefore hypothesised that neonatal overfeeding would alter the ability of hippocampal microglia to respond to an immune challenge with lipopolysaccharide (LPS) and that concomitant minocycline, a tetracycline antibiotic that suppresses microglial activity, could restore these responses. We induced neonatal overfeeding by manipulating the litter sizes in which Wistar rat pups were raised, so the pups were suckled in litters of four (neonatally overfed) or 12 (control‐fed). We then examined the hippocampal microglial profiles 24 hour after an immune challenge with LPS and found that the neonatally overfed rats had dramatically increased microglial numbers in the hippocampus after immune challenge compared to control‐fed rats. Attempts to reverse these effects with minocycline revealed repeated that neonatal injections, whether with minocycline or with saline, markedly suppressed microglial number and density throughout the hippocampus and abolished the difference between the groups in their responses to LPS. These data suggest that neonatal overfeeding not only can have lasting effects on hippocampal immune responses, but also that neonatal exposure to a protocol of repeated injections, irrespective of treatment, has a pronounced long‐term impact, highlighting the importance of considering these effects when interpreting experimental data.     

Prenatal intracranial hemorrhage and neurologic complications in alloimmune thrombocytopenia.

Neonatal alloimmune thrombocytopenia results from platelet-antigen incompatibility between mother and fetus, leading to antibody-mediated destruction of fetal platelets. With a prevalence of 1 in 1000 births, approximately 4000 infants born in the United States each year develop neonatal alloimmune thrombocytopenia. Ten to 20% of affected neonates develop intracranial hemorrhage, with 25 to 50% occurring prenatally. We report three infants who developed prenatal hemorrhage. One died in utero, and the other two had cerebral porencephaly and neurologic deficits. Infants with neonatal alloimmune thrombocytopenia have elevated risks of perinatal death and neurologic complications, including cerebral palsy, hypotonia, cortical blindness, developmental delay, seizures, and psychomotor retardation. We also report our retrospective review of the New England Medical Center neonatal intensive care unit between 1990 and 1999. Using current management guidelines, including treatment of the mother with a weekly infusion of high-dose (1-2 g/kg) intravenous immunoglobulin and/or corticosteroids, all eight infants with neonatal alloimmune thrombocytopenia did well.     

Neonatal immune challenge induces female-specific changes in social behavior and somatostatin cell number

Decreases in social behavior are a hallmark aspect of acute “sickness behavior” in response to infection. However, immune insults that occur during the perinatal period may have long-lasting consequences for adult social behavior by impacting the developmental organization of underlying neural circuits. Microglia, the resident immune cells of the central nervous system, are sensitive to immune stimulation and play a critical role in the developmental sculpting of neural circuits, making them likely mediators of this process. Here, we investigated the impact of a postnatal day (PND) 4 lipopolysaccharide (LPS) challenge on social behavior in adult mice. Somewhat surprisingly, neonatal LPS treatment decreased sociability in adult female, but not male mice. LPS-treated females also displayed reduced social interaction and social memory in a social discrimination task as compared to saline-treated females. Somatostatin (SST) interneurons within the anterior cingulate cortex (ACC) have recently been suggested to modulate a variety of social behaviors. Interestingly, the female-specific changes in social behavior observed here were accompanied by an increase in SST interneuron number in the ACC. Finally, these changes in social behavior and SST cell number do not appear to depend on microglial inflammatory signaling, because microglia-specific genetic knock-down of myeloid differentiation response protein 88 (MyD88; the removal of which prevents LPS from increasing proinflammatory cytokines such as TNFα and IL-1β) did not prevent these LPS-induced changes. This study provides novel evidence for enduring effects of neonatal immune activation on social behavior and SST interneurons in females, largely independent of microglial inflammatory signaling.     

Long-Term Consequences of Neonatal Injury

The maturation of the central nervous system’s (CNS’s) sensory connectivity is driven by modality-specific sensory input in early life. For the somatosensory system, this input is the physical, tactile interaction with the environment. Nociceptive circuitry is functioning at the time of birth; however, there is still considerable organization and refinement of this circuitry that occurs postnatally, before full discrimination of tactile and noxious input is possible. This fine-tuning involves separation of tactile and nociceptive afferent input to the spinal cord’s dorsal horn and the maturation of local and descending inhibitory circuitry. Disruption of that input in early postnatal life (for example, by tissue injury or other noxious stimulus), can have a profound influence on subsequent development, and consequently the mature functioning of pain systems. In this review, the impact of neonatal surgical incision on nociceptive circuitry is discussed in terms of the underlying developmental neurobiology. The changes are complex, occurring at multiple anatomical sites within the CNS, and including both neuronal and glial cell populations. The altered sensory input from neonatal injury selectively modulates neuronal excitability within the spinal cord, disrupts inhibitory control, and primes the immune system, all of which contribute to the adverse long-term consequences of early pain exposure.     

Neonatal seizures

In childhood, the risk for seizures is greatest in the neonatal period. Currently used therapies have limited efficacy. Although the treatment of neonatal seizures has not significantly changed in the past several decades, there has been substantial progress in understanding developmental mechanisms that influence seizure generation and responsiveness to anticonvulsants. This review includes an overview of current approaches to the diagnosis and treatment of neonatal seizures, identifies some of the critical factors that have limited progress, and highlights recent insights about the pathophysiology of neonatal seizures that may provide the foundation for better treatment.     

Neonatal programming of neuroimmunomodulation--role of adipocytokines and neuropeptides

Programming is an epigenetic phenomenon by which nutrition, environment and stress acting in a critical period earlier in life change the organism's development. This process was evolutionarily selected as an adaptive tool for the survival of organisms living in nutritionally deficient areas and submitted to stressful conditions. Thus, perinatal malnutrition turns on different genes that provide the organism with a thrifty phenotype. In conditions of abundant supply of nutrients, those programmed organisms can be at risk of developing metabolic diseases (obesity, dyslipidemia, diabetes and hypertension). How nutrition or neonatal stress can program the immune system is less well known. Here, we discuss some of the hormonal and metabolic changes that occur in mothers and neonates and how those factors can imprint hormonal or metabolic changes that program neuroimmunomodulatory effects. Some of these changes involve thyroid hormones, leptin, insulin, glucocorticoids and prolactin as potential imprinting factors. Most of them can be transferred through the milk and may change with malnutrition or stress. We discuss the programming effects of these hormones upon body weight, body composition, insulin action, thyroid, adrenal and immune and inflammatory responses, with special emphasis on leptin, a cytokine that seems to play a central role in these events.     

Neonatal swallowing assessment and practical recommendations for oral feeding in a girl with a severe congenital myopathy

The investigators report the case of a 6-week-old girl with a cap-like congenital myopathy and frequent coughing during feeding. Neonatal swallowing assessments were performed with surface electromyography of the submental muscle group and nasal airflow during sucking and swallowing. A videofluoroscopic swallow study was performed separately. The registration of swallowing and breathing revealed a highly coordinated sequence of sucking, swallowing, and breathing. However, after a series of sucking and swallowing there was residue in the hypopharyngeal area, causing laryngeal penetration and coughing. Based on the findings, specific recommendations such as the use of a soft nipple, diminished suck-swallow sequences, and limited feeding time were made for this girl. These proved to be appropriate to prevent coughing as a signal of penetration or aspiration of milk during swallowing. This case highlights the profit of neonatal swallowing assessment, which can provide recommendations for safe oral feeding.     

Neonatal host astrocyte migration into xenogeneic cerebral cortical grafts.

Migration of host astrocytes into grafts was investigated by transplantation of rat cortex (E16) into the cortex or midbrain of neonatal mice. Host astrocytes, visualized by the mouse astrocyte-specific antibody, began to invade the grafted cortex during the first week post-transplantation and sequentially migrated substantial distances throughout the graft. Host cells in the grafts which were undergoing immune rejection became hypertrophic. These results have important implications when assessing interactions between host and graft cells.     

Neonatal levels of acute phase proteins and later risk of non-affective psychosis

Mounting evidence suggests that immune disturbances in early life may be implicated in the etiology of non-affective psychoses. Our aim was to assess the levels of neonatal acute phase proteins (APPs), central to innate immune function as well as central nervous system development, in neonatal dried blood spots and their association with later risk of non-affective psychoses. This case-control study included 196 individuals with a verified register-based diagnosis of non-affective psychosis and 502 controls matched on age, sex and hospital of birth. Concentrations of nine different APPs were measured in eluates from dried blood spots using a bead-based multiplex assay. Odds ratios (OR) for non-affective psychoses were calculated for log₂-transformed (continuous) as well as tertiles of APP concentrations. In continuous analysis, higher concentrations of two APPs, tissue plasminogen activator (tPA; OR: 0.90, 95% confidence interval (CI): 0.85–0.96) and serum amyloid P (SAP; OR: 0.88, 95% CI: 0.78–0.99) were protective in terms of risk of non-affective psychosis. These relationships were not affected by the addition of covariates relevant to maternal health, pregnancy and delivery to the model. Tertile analysis confirmed a protective relationship for higher levels of tPA and SAP, as well as for procalcitonin (highest tertile OR: 0.54, 95% CI:0.32–0.91). Our results suggest that persons who develop non-affective psychoses have lower levels of certain APPs at the time of birth. These differences may render individuals more susceptible to infectious diseases or cause deficiencies in pathways critical for neurodevelopment.     

CNS siderosis and dandy-walker variant after neonatal alloimmune thrombocytopenia

This report presents a case of superficial siderosis of the central nervous system secondary to repeated intraventricular and subarachnoid bleeding of a newborn infant with neonatal alloimmune thrombocytopenia. In addition, this infant manifested Dandy-Walker variant. To date, the few known cases of superficial siderosis in neonates have not been associated with neonatal alloimmune thrombocytopenia or Dandy-Walker complex. We believe that repeated bleeding in the central nervous system from early fetal life, especially in the posterior fossa, may produce cerebellar atrophy as occurs in adults with superficial siderosis of the central nervous system.